PROJECT SUMMARY ? RESEARCH PROJECT: PATHOLOGIC SIGNIFICANCE OF MATERNAL AUTOANTIBODIES Autism spectrum disorder (ASD) affects about 1 in 59 children in the United States, yet there remains relatively little understanding of underlying cause(s) and few options for therapeutic interventions. Our research team is evaluating an immune-based mechanism implicated in ASD ? prenatal exposure to maternal autoantibodies that target proteins in the developing fetal brain. A significant subset of mothers who have a child with ASD produce antibodies to fetal brain proteins that are critical for neurodevelopment. We hypothesize that these antibodies cross the placenta during gestation, interact with fetal brain protein targets, alter neurodevelopment, and lead to a maternal autoantibody (AB) related (MAR) form of ASD. We have found that up to 26% of cases are associated with MAR. Previous preclinical studies have used mice and nonhuman primates to evaluate the pathogenic importance of MAR exposure. In these model systems, offspring born to dams periodically injected with MAR AB during gestation exhibit atypical neurodevelopment and behavior. While these passive transfer models provide support for MAR as a risk factor for ASD, they do not reflect the constant exposure that occurs throughout gestation experienced by the human fetus. Our research team has recently validated a highly accurate test for MAR AB, and established the next generation of more sophisticated antigen-driven models, which together will allow us to evaluate the pathogenic significance of continuous exposure to specific combinations of MAR AB. We are now positioned to utilize the sophisticated social and cognitive processing capabilities and complex neuroanatomy of the rat model system to evaluate the pathogenic significance of prenatal MAR exposure. Here we propose an exploratory, discovery-based, research project that will utilize multiple MIND Institute IDDRC Cores to test the hypothesis that continuous gestational exposure to specific combinations of MAR AB is causally linked to changes in brain and behavioral development of the offspring. Through human clinical studies, we will first determine the association between the MAR ASD AB patterns and neurodevelopmental profiles among the children with ASD from human samples collected prospectively during pregnancy from high-risk mothers (Aim 1). We will then leverage these clinically relevant data to directly assess the pathologic significance of prenatal exposure to epitope-specific AB in generating ASD-relevant behaviors in the antigen-driven rat model (Aim 2). Data derived from Aim 2 will indicate which of the individual ABs are pathologically significant, and which are biomarkers of risk with no pathologic relevance. In this model, the embryos will be continuously exposed to the MAR ABs throughout gestation, thereby better representing the human MAR ASD environment and providing an experimental model system to determine downstream molecular pathways (Aim 3). This high-risk, potentially high-reward, proposal is an essential next step in developing novel therapeutics and strategies for prevention.